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Definitions

• the subject of the invention is alkylthiazole carbamate derivatives, their preparation and their therapeutic application.
• a first subgroup of compounds is composed of compounds for which R 2 represents a hydrogen atom.
• a second subgroup of compounds is composed of compounds for which n represents an integer equal to 1 or 2 and m represents an integer equal to 2.
• a third subgroup of compounds is composed of compounds for which A represents a C 1-8 -alkylene group, more particularly a methylene or ethylene group.
• a fourth subgroup of compounds is composed of compounds for which R 1 represents a group R 5 optionally substituted by one or more R 6 and / or R 7 groups ;
• R 5 represents a pyridinyl or quinolinyl group;
• R 6 represents a halogen atom, more particularly a chlorine or fluorine atom, a cyano group, -CH 2 CN, C 1-6 -alkyl, more particularly methyl, isopropyl, isobutyl, C 1-6 -alkoxy, more particularly methoxy, ethoxy, C 1-6 -haloalkyl, more particularly trifluoromethyl, C 3-7 -cycloalkyl, more particularly cyclohexyl, C 3-7 -cycloalkyl-C 1-3 -alkylene-O-, more particularly cyclopropyl-CH 2 -O-, NR 8 R 9 , NR 8 COR 9 , NR 8 CO 2 R 9 ,
• a fifth subgroup of compounds is composed of compounds for which R 3 represents a hydrogen atom, a C 1-6 alkyl group, more particularly methyl, or a trifluoromethyl group.
• a sixth subgroup of compounds is composed of compounds for which R 4 represents a thiazole optionally substituted by one or more substituents chosen from a halogen atom, more particularly from chlorine, a group C 1-6 -alkyl, more particularly methyl, C 1-6 -haloalkyl, more particularly trifluoromethyl, pyridinyl, CONR 8 R 9 ; R 8 and R 9 represent, independently of one another, a hydrogen atom or a C 1-6 alkyl group, more particularly a methyl.
• a seventh subgroup of compounds is constituted by the compounds of general formula (I) in which both R 1 and / or R 2 and / or R 3 and / or R 4 and / or n and / or m and / or A are as defined in the groups above.
• the compounds of general formula (I) may comprise one or more asymmetric carbons. They can exist as enantiomers or diastereoisomers.
• the compounds of general formula (I) may also exist in the form of cis (Z) or trans (E) stereoisomers. These stereoisomers, enantiomers and diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
• the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
• salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
• the compounds of the invention can be prepared according to various methods, illustrated by the following diagrams.
• a first method (scheme 1) consists of reacting an amine of general formula (II), in which A, R 1 , R 2 , m and n are as defined in the general formula (I) defined above, with a carbonate of general formula (III) in which Z represents a hydrogen atom or a nitro group, R 3 and R 4 are as defined in the general formula (I) defined above, in the presence of a base such as triethylamine, pyridine, N, N- dimethylaminopyridine or diisopropylethylamine, in a solvent such as toluene or dichloroethane, at a temperature between room temperature and the reflux temperature of the solvent.
• a base such as triethylamine, pyridine, N, N- dimethylaminopyridine or diisopropylethylamine
• An alternative for obtaining the compounds of general formula (I) (scheme 1) consists in reacting an amine of general formula (II), as defined above, with phenyl or 4-nitro-phenyl chloroformate, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at a temperature between 0 ° C and room temperature, to yield the carbamate derivative of general formula (IV), in which A, R 1 , R 2 , m and n are as defined in the general formula (I) defined above, and Z represents a hydrogen atom or a nitro group.
• a base such as triethylamine or diisopropylethylamine
• a solvent such as dichloromethane or tetrahydrofuran
• the carbamate derivative of general formula (IV) thus obtained is then converted into a compound of general formula (I) by the action of an alcohol of general formula HOCHR 3 R 4 (IIIa), in which R 3 and R 4 are such that defined in the general formula (I) defined above, in the presence of a base such as triethylamine, pyridine, N, N- dimethylaminopyridine or diisopropylethylamine, in a solvent such as toluene or dichloroethane, at a temperature between room temperature and the reflux temperature of the solvent.
• a base such as triethylamine, pyridine, N, N- dimethylaminopyridine or diisopropylethylamine
• a second method (Scheme 2) consists in reacting, in a first step, an amine of general formula (IIa), in which A, R 2 , m and n are as defined in the general formula (I) defined above, and PG represents a protecting group such as a Boc (tert-butyloxycarbonyl), a Cbz (benzyloxycarbonyl), a benzyl or a benzhydrile, with a carbonate of general formula (III) as defined above, under the conditions described herein.
• an amine of general formula (IIa) in which A, R 2 , m and n are as defined in the general formula (I) defined above, and PG represents a protecting group such as a Boc (tert-butyloxycarbonyl), a Cbz (benzyloxycarbonyl), a benzyl or a benzhydrile, with a carbonate of general formula (III) as defined above, under the conditions described herein.
• An embodiment for obtaining intermediates of general formula (Ia) (scheme 2) consists in reacting an amine of general formula (IIa), as defined above, with phenyl or 4-nitro-phenyl chloroformate, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at a temperature of between 0 ° C. and room temperature to yield the carbamate derivative of the general formula (IVa), wherein A, R 2 , m and n are as defined in the general formula (I) defined above, PG is as defined above and Z represents a hydrogen atom or a nitro group.
• the carbamate derivative of general formula (IVa) thus obtained is then converted into a compound of general formula (Ia) by the action of an alcohol of general formula HOCHR 3 R 4 (IIIa), as defined above, in the presence of a base such as triethylamine, pyridine, N, N- dimethylaminopyridine or diisopropylethylamine, in a solvent such as toluene or dichloroethane, at a temperature between room temperature and the reflux temperature of the solvent, followed by a deprotection reaction, for example in the presence of a solution of hydrochloric acid (5N) in isopropanol or dioxane.
• a base such as triethylamine, pyridine, N, N- dimethylaminopyridine or diisopropylethylamine
• solvent such as toluene or dichloroethane
• the compound of general formula (I) is then obtained by reaction of the compound of general formula (Ia) with a derivative of general formula (V), in which R 1 is as defined in general formula (I) and U 1 represents a halogen atom or an O-triflate group, using the conditions of aromatic or heteroaromatic nucleophilic substitution reactions, for example by means of a base such as triethylamine, diisopropylethylamine, pyridine or N, N- dimethylaminopyridine; in a solvent such as dichloromethane, dichloroethane, acetonitrile, N, N- dimethylformamide, dioxane or tetrahydrofuran, at a temperature between 0 ° C and the reflux temperature of the solvent.
• This transformation can also be carried out using the N- arylation or N- heteroarylation conditions of Buchwald, for example by means of a palladium or copper catalyst.
• An embodiment for obtaining intermediates of general formula (Ib) (Scheme 2) consists in reacting at first an amine of general formula (IIb), in which A, R 5 , R 2 , m and n are such that defined in the general formula (I) defined above, and U 2 is as defined above, with a carbonate of general formula (III) as defined above, under the conditions described above during the reaction of the formula amine general (II) with the carbonate of general formula (III), to obtain the intermediate of general formula (Ib), in which A, R 5 , R 2 , R 3 , R 4 , m and n are as defined in the general formula (I), and U 2 is as defined above.
• the carbonate of general formula (III) can be prepared according to any method described in the literature, for example by reaction of an alcohol of general formula HOCHR 3 R 4 (IIIa), in which R 3 and R 4 are such that defined in the general formula (I) as defined above, with phenyl or 4-nitrophenyl chloroformate, in the presence of a base such as triethylamine, N- methylmorpholine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at a temperature between 0 ° C and room temperature.
• a base such as triethylamine, N- methylmorpholine or diisopropylethylamine
• a solvent such as dichloromethane or tetrahydrofuran
• Example 1 The procedure is as described in Example 1 (step 1.4.). From 0.3 g (1.07 mmol) of 2- [5 '- (4-fluoro-phenyl) -3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl-4- yl] ethylamine, described in Example 1 (step 1.3), of 0.35 g (1.18 mmol) of thiazol-2-ylmethyl (4-nitro-phenyl) -carbonate ( EP486948A2 ) and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 0.25 g of pure product in the form of a white powder is obtained.
• Example 1 The procedure is as described in Example 1 (step 1.4.). From 0.16 g (0.53 mmol) of 2- [5 '- (4-fluoro-phenyl) -3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl-4- yl] -ethylamine, described in Example 1 (step 1.3.), 0.22 g (0.8 mmol) (4-nitro-phenyl) -carbonate thiazol-5-ylmethyl, and after chromatography on silica gel eluting with a 40/60 mixture of ethyl acetate and cyclohexane, 0.180 g of pure product is obtained in the form of a white powder.
• step 1.3 The procedure is as described in Example 1 (step 1.3). From 1.3 g (3.03 mmol) of 2- ⁇ 2- [6 '- (4-fluoro-phenyl) -3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl) 4-yl] ethyl ⁇ -isoindole-1,3-dione, prepared in step 4.2. and 0.485 g (15.13 mmol) of hydrazine monohydrate, 0.8 g of product is obtained in the form of a colorless liquid used as such in the next step.
• aqueous phase is separated off, extracted twice with ethyl acetate, the combined organic phases are successively washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution and dried. on sodium sulphate. After evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 2.33 g of product are obtained in the form of a beige solid. Mp (° C): 90-92 ° C 4.6.
• Example 4 The procedure is as described in Example 4 (step 4.5). From 1 g (8.84 mmol) of thiazole-4-carboxaldehyde, 0.10 ml (0.10 mmol) of a solution of tetrabutylammonium fluoride 1M in THF, 1.38 g (9, 72 mmol) of trifluoromethyltrimethylsilane (TMS-CF 3 ), and after chromatography on silica gel eluting with a 98/2 mixture of dichloromethane and methanol, 0.54 g of pure product is obtained in the form of a colorless oil.
• TMS-CF 3 trifluoromethyltrimethylsilane
• Example 4 The procedure is as described in Example 4 (step 4.6). Starting from 0.183 g (1 mmol) of 2- [6 '- (4-fluoro-phenyl) -3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl-4-yl] -ethylcarbamate of 4-nitro-phenyl, described in Example 4 (step 4.4.), 0.19 g (1.5 mmol) of N, N- diisopropylethylamine, 0.006 g (0.05 mmol) of N, N - dimethylaminopyridine 0.51 g (1.1 mmol) of 2,2,2-trifluoro-1-thiazol-4-yl-ethanol, obtained in step 5.1, and after chromatography on silica gel eluting.
• Example 4 The procedure is as described in Example 4 (step 4.5). From 2 g (17.68 mmol) of thiazole-5-carboxaldehyde, 0.88 ml (0.88 mmol) of a 1M solution of tetrabutylammonium fluoride in THF, 2.765 g (19.44 mmol) ) of trifluoromethyltrimethylsilane (TMS-CF 3 ), and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 2.23 g of pure product is obtained in the form of a colorless oil.
• TMS-CF 3 trifluoromethyltrimethylsilane
• the compounds of the invention have been the subject of pharmacological tests to determine their effect.
• inhibitor of the enzyme FAAH Fatty Acid Amido Hydrolase
• the inhibitory activity was demonstrated in a radioenzymatic test based on measuring the product of hydrolysis of anandamide [ethanolamine 1- 3 H] by FAAH ( Life Sciences (1995), 56, 1999-2005 and Journal of Biochemical and Biophysical Methods (2004), 60 (2), 171-177 ).
• mouse brains minus the cerebellum
• the enzymatic reaction is carried out in 96 well Multiscreen filtration plates in a final volume of 70 ⁇ l.
• Reaction buffer supplemented with bovine serum albumin without fatty acids (BSA, 1 mg / ml) was used for the enzymatic reaction, the dilution of the compounds and of anandamide [ethanolamine 1- 3 H].
• BSA bovine serum albumin without fatty acids
• the reaction is started by addition of anandamide [ethanolamine 1- 3 H] (specific activity 15-20 Ci / mmol) diluted with cold anandamide (10 ⁇ l / well, final concentration of 10 ⁇ M, 0.01 ⁇ Ci per test).
• anandamide [ethanolamine 1- 3 H] (specific activity 15-20 Ci / mmol) diluted with cold anandamide (10 ⁇ l / well, final concentration of 10 ⁇ M, 0.01 ⁇ Ci per test).
• the enzymatic reaction is stopped by adding a solution of 5M activated charcoal prepared in 1.5M NaCl buffer and 0.5M HCl (50 ⁇ l / well). The mixture is stirred for 10 minutes then the aqueous phase containing ethanolamine [ 1-3 H] is recovered by vacuum filtration and counted by liquid scintillation.
• the most active compounds of the invention have IC 50 (concentration inhibiting by 50% the enzymatic control activity of FAAH) of between 0.001 and 1 ⁇ M, for example compounds no. IC 50 values of 0.003 and 0.007 ⁇ M respectively. It therefore appears that the compounds according to the invention have an inhibitory activity on the FAAH enzyme.
• the subject of the invention is also medicaments which comprise a compound of formula (I), or an addition salt with an acid, or a pharmaceutically acceptable hydrate or solvate of the compound of formula (I).
• These drugs find their use in therapy, especially in the treatment of the above-mentioned pathologies.
• the present invention relates to pharmaceutical compositions containing, as active ingredient, at least one compound according to the invention.
• These pharmaceutical compositions contain an effective dose of a compound according to the invention, or an addition salt with an acid, or a hydrate, or a pharmaceutically acceptable solvate of said compound, and optionally one or more pharmaceutically acceptable excipients.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, oral, Intratracheal, intraocular, intranasal, inhalation, subcutaneous, intramuscular or intravenous administration forms and rectal or vaginal administration forms.
• oral forms such as tablets, soft or hard capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, oral, Intratracheal, intraocular, intranasal, inhalation, subcutaneous, intramuscular or intravenous administration forms and rectal or vaginal administration forms.
• the compounds according to the invention can be used in creams, ointments or lotions.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

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• 2008
  • 2008-07-23 FR FR0804179A patent/FR2934265B1/fr not_active Expired - Fee Related
• 2009
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• 2011
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• 2013
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